The pantothenic acid derivative dexpanthenol ameliorated doxorubicin-induced neurotoxicity via regulating AKT/CREB/BDNF and AKT/NRF2 signaling pathways.

BACKGROUND

Doxorubicin (Dox)-induced neurotoxicity is a well-documented side effect of chemotherapy. Dexpanthenol (Dex), an analog of vitamin B5, has shown protective properties. This study aimed to explore the molecular mechanisms by which Dex mitigates Dox-induced neurotoxicity, particularly through the protein kinase B (AKT)/cyclic AMP-response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway and nuclear factor erythroid 2-related factor 2 (NRF2) signaling.

METHODS AND

RESULTS

The experiment was conducted using four groups: control, Dex, Dox, and Dox + Dex, comprising a total of 32 female Wistar Albino rats. After two weeks of treatment, the rats were euthanized, and brain and cerebellum tissues were collected for analysis. Biochemical analysis was performed spectrophotometrically to assess oxidative stress parameters, while histological and immunostaining analyses focused on nuclear factor kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) immunoexpressions. Genetic analysis of AKT, CREB, BDNF, and NRF2 gene expressions was conducted using real-time polymerase chain reaction. Histopathological evaluation of the Dox group revealed hyperemia, microhemorrhage, neuronal damage, and neuronophagia. Additionally, an increase in caspase-3, tumor necrosis factor-alpha, NF-κB, and iNOS immunoexpressions were observed, along with elevated total oxidant status and oxidative stress index. A decrease in AKT, CREB, BDNF, and NRF2 gene expressions accompanied these changes. Dex treatment significantly reversed these pathological findings, effectively protecting the brain from Dox-induced neuronal damage.

CONCLUSION

In conclusion, Dex may provide neuroprotection in female rats with Dox-induced neurotoxicity by activating the CREB/BDNF pathway and reducing oxidative stress through AKT-mediated NRF2 synthesis. Further detailed studies exploring additional pathways are required to incorporate Dex into cancer treatment protocols and minimize side effects.